1. Field of the Invention
The present invention relates generally to the delivery of antibiotics to mammals for use in the treatment of intracellular pathogens. More particularly, the present invention involves the coupling of antibiotics to transferrin to form antibiotic-transferrin conjugates which target pathogens that reside in membrane-bound phagosomes.
2. Description of Related Art
The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the appended bibliography.
M. tuberculosis is an intracellular pathogen that parasitizes human mononuclear phagocytes. Throughout its life cycle in these host cells, M. tuberculosis resides and multiplies in a membrane-bound phagosome that resists acidification and fusion with lysosomes (1-4). In previous studies, using quantitative immunoelectron microscopy, the composition and maturation of the M. tuberculosis phagosome, focusing on known markers of the endocytic pathway have been examined (4). These studies revealed that the M. tuberculosis phagosome exhibits delayed clearance of MHC class I molecules, relatively intense staining for MHC class II molecules and the endosomal marker transferrin receptor, and relatively weak staining for the lysosome-associated membrane glycoproteins CD63, LAMP-1, and LAMP-2 and the lysosomal acid protease, cathepsin D. Like M. tuberculosis, wild-type Legionella pneumophila inhibits phagosome-lysosome fusion and phagosome acidification (5,6). However, in contrast to the M. tuberculosis phagosome, the L. pneumophila phagosome rapidly clears MHC class I molecules and excludes MHC class II molecules as well as all endosomal-lysosomal markers studied (4,7,8). In contrast to the phagosomes containing either live M. tuberculosis or L. pneumophila, phagosomes containing heat-killed M. tuberculosis or polystyrene beads fuse with lysosomes and stain intensely for lysosome-associated membrane glycoproteins and cathepsin D (4).
There are a number of treatment protocols which are presently being used to treat M. tuberculosis and other intracellular pathogens. Many of these protocols involve the use of one or more antibiotic compositions. As in any treatment which utilizes antibiotics, it is desirable to introduce the antibiotic in vivo in such a way as to maximize the effectiveness of the antibiotic against the pathogen. Accordingly, there has been a continuing search to provide new and improved delivery vehicles and systems wherein the efficacy of an antibiotic with respect to a given pathogen is maximized.